Survival In Osteosarcoma Research Articles

Inhibiting DNA-PKCS radiosensitizes human osteosarcoma cells

Osteosarcoma survival rate has not improved over the past three decades, and the debilitating side effects of the surgical treatment suggest the need for alternative local control approaches. Radiotherapy is largely ineffective in osteosarcoma, indicating a potential role for radiosensitizers. Blocking DNA repair, particularly by inhibiting the catalytic subunit of DNA-dependent protein kinase (DNA-PKCS), is an attractive option for the radiosensitization of osteosarcoma. In this study, the expression of DNA-PKCS in osteosarcoma tissue specimens and cell lines was examined. Moreover, the small molecule DNA-PKCS inhibitor, KU60648, was investigated as a radiosensitizing strategy for osteosarcoma cells in vitro. DNA-PKCS was consistently expressed in the osteosarcoma tissue specimens and cell lines studied. Additionally, KU60648 effectively sensitized two of those osteosarcoma cell lines (143B cells by 1.5-fold and U2OS cells by 2.5-fold). KU60648 co-treatment also altered cell cycle distribution and enhanced DNA damage. Cell accumulation at the G2/M transition point increased by 55% and 45%, while the percentage of cells with >20 γH2AX foci were enhanced by 59% and 107% for 143B and U2OS cells, respectively. These results indicate that the DNA-PKCS inhibitor, KU60648, is a promising radiosensitizing agent for osteosarcoma.

BRCA1-Associated Protein-1 Suppresses Osteosarcoma Cell Proliferation and Migration Through Regulation PI3K/Akt Pathway.

BRCA1-associated protein-1 (BAP1) is an important nuclear-localized deubiquitinating enzyme. Dysregulation of BAP1 has been reported in many types of cancers. However, there are few articles on the role of BAP1 in osteosarcoma (OS) and the molecular mechanisms of BAP1 in OS remain largely unknown. In this study, we examined the expression of BAP1 in the tissue sample from OS patients and healthy control subjects, and then investigated the biological function and molecular mechanisms of BAP1 in OS. We found that BAP1 was significantly reduced in OS patients and OS cell lines. Then we found that BAP1 has a key role in OS cell proliferation, apoptosis, migration, and invasion. Furthermore, we found that BAP1 exerted its influence on the PI3K/Akt signaling pathway and there was physical association between BAP1 and miR-125. In conclusion, our data highlight the important roles of BAP1 in the survival of OS. It may be a potential therapy for OS.

Andrographolide Induces Autophagic Cell Death and Inhibits Invasion and Metastasis of Human Osteosarcoma Cells in An Autophagy-Dependent Manner

Background/Aims: Osteosarcoma (OS) is the most common primary malignant tumor of bone tissue. Although treatment effectiveness has improved, the OS survival rate has fluctuated in recent years. Andrographolide (AG) has been reported to have antitumor activity against a variety of tumors. Our aim was to investigate the effects and potential mechanisms of AG in human osteosarcoma. Methods: Cell viability and morphological changes were assessed by MTT and live/dead assays. Apoptosis was detected using Annexin V-FITC/PI double staining, DAPI, and caspase-3 assays. Autophagy was detected with mRFP-GFP-LC3 adenovirus transfection and western blot. Cell migration and invasion were detected by wound healing assay and Transwell® experiments. Results: AG dose-dependently reduced the viability of osteosarcoma cells. No increase in apoptosis was detected in AG-treated human OS MG-63 and U-2OS cells, and the pan-caspase inhibitor z-VAD did not attenuate AG-induced cell death. However, AG induced autophagy by suppressing PI3K/Akt/mTOR and enhancing JNK signaling pathways. 3-MA and Beclin-1 siRNA could reverse the cytotoxic effects of AG. In addition, AG inhibited the invasion and metastasis of OS, and this effect could be reversed with Beclin-1 siRNA. Conclusion: AG inhibits viability and induces autophagic death in OS cells. AG-induced autophagy inhibits the invasion and metastasis of OS.

Systemic therapy for bone sarcomas

Bone sarcomas comprise less than 0.2% of all malignancies and are divided into several subtypes with varying sensitivities to systemic therapy. While the role of adjuvant chemotherapy in the management of soft-tissue sarcomas is controversial, perioperative chemotherapy has greatly improved the survival of nonmetastatic Ewing sarcoma and osteosarcoma. However, metastatic unresectable Ewing sarcoma and osteosarcoma are still associated with a poor prognosis. Giant cell tumor of bone and chordoma are refractory to conventional cytotoxic chemotherapy, but in recent years targeted therapy has been shown to be able to provide a degree of control of unresectable disease. Conventional chondrosarcoma remains refractory to systemic therapy, although the less common subtypes, dedifferentiated and mesenchymal chondrosarcomas, can be sensitive to chemotherapy but still have a poor prognosis.

Osteosarcoma of the Mandible: A Site-Specific Study on Survival and Prognostic Factors.

Osteosarcoma of head and neck is a rare condition comprising of <1% of all head and neck cancers, retrospective studies show difference in survival of mandibular osteosarcoma to other head and neck sites, necessitating investigation into site-specific survival and recurrence rates.

Clinico-pathological Study of Limb Salvage Surgery for Osteosarcoma: Experience in a Rural Cancer Center.

Although recent multimodality therapeutic protocols have led to improved survival in osteosarcoma (OS), the outcome still remains dismal. Ongoing international multicentric trials on OS aim to randomize patients for optimum management, based on histological response to NACT. The pathologic response to neoadjuvant chemotherapy (NACT) is the most important factor predicting prognosis. In this study of 23 cases of limb salvage surgery post neoadjuvant chemotherapy, mean age was 18.3years, with male predominance. 65.5% cases were conventional OS. Histologic assessment of chemotherapeutic effect done by Huvos grading revealed good response (Huvos lll and lV) in 15 (65.2%) and poor response (Huvos l and ll) in eight (34.8%). A scoring based on MRI with a scale of 1-6 was compared with histologic response. Five (62.5%) of poor responders showed score of >3 and 73.3% of good responders showed ≤3. Dose intensity of NACT was calculated and correlated with the histological response. 53.3% of good responders showed ARDI>0.9. Five (21.7%) developed local recurrence and 10(43.4%) had pulmonary metastasis. Adoption of more aggressive treatment modalities may ensure better histologic response and longer event free survival.

Candidate germline polymorphisms of genes belonging to the pathways of four drugs used in osteosarcoma standard chemotherapy associated with risk, survival and toxicity in non-metastatic high-grade osteosarcoma

This study aimed to identify associations between germline polymorphisms and risk of high-grade osteosarcoma (HGOS) development, event-free survival (EFS) and toxicity in HGOS patients treated with neo-adjuvant chemotherapy and surgery.Germline polymorphisms of 31 genes known to be relevant for transport or metabolism of all four drugs used in HGOS chemotherapy (methotrexate, doxorubicin, cisplatin and ifosfamide) were genotyped in 196 patients with HGOS and in 470 healthy age and gender-matched controls. Of these 196 HGOS patients, a homogeneously treated group of 126 patients was considered for survival analyses (survival cohort). For 57 of these, treatment-related toxicity data were available (toxicity cohort).Eleven polymorphisms were associated with increased risk of developing HGOS (p < 0.05). The distribution of polymorphisms in patients was characterized by a higher Shannon entropy. In the survival cohort (n = 126, median follow-up = 126 months), genotypes of ABCC2_1249A/G, GGH_452T/C, TP53_IVS2+38G/C and CYP2B6*6 were associated with EFS (p < 0.05). In the toxicity cohort (n = 57), genotypes of ABCB1_1236T/C, ABCC2_1249A/G, ABCC2_3972A/G, ERCC1_8092T/G, XPD_23591A/G, XRCC3_18067T/C, MTHFR_1298A/C and GGH_16T/C were associated with elevated risk for toxicity development (p < 0.05).The results obtained in this retrospective study indicate that the aforementioned germline polymorphisms significantly impact on the risk of HGOS development, EFS and the occurrence of chemotherapy-related toxicity. These findings should be prospectively validated with the aim of optimizing and tailoring HGOS treatment in the near future.

Abstract 4134: Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma

Abstract Purpose: Over the past four decades, osteosarcoma (OS) survival rates have remained stagnant. There is a need to identify novel therapies to target OS. In this study we examined the expression of Programed Death Ligand 1 (PD-L1) and defined the tumor microenvironment in OS in order to assess the feasibility of utilizing immune checkpoint inhibitors as a treatment modality. Experimental Design: PD-L1 expression in OS was examined in two patient cohorts using immunohistochemistry (IHC) (n = 48, n = 59) and expression was validated using quantitative real time PCR (qRT-PCR) (n = 21) and western blotting (n = 9). IHC was used to determine presence of tumor infiltrating lymphocytes and antigen presenting cells (APCs) in the tumor. Expression of PD-L1 was correlated with the presence of immune cells and with event free survival in OS. Results: PD-L1 is expressed in up to 25% of primary OS tumors. Of the PD-L1 positive tumors the majority were also PD-1 positive (92% vs 8%, p = 0.002). In addition, the presence of immune cells in the tumor mass was significantly associated with PD-L1 expression. Although all immune cell types examined were present in OS, only infiltration by APCs, specifically CD1a positive dendritic cells (48.6% vs. 51.4%, p = 0.0010) and CD68 positive macrophages (70.3% vs. 29.7%, p = 0.0316), was associated with worse outcomes. PD-L1 expression was significantly associated with worsened survival (21.6% pos. vs. 78.4% neg., p = 0.0146). Conclusions: For the first time we have identified PD-L1 expression or presence of CD1a or CD68 positive antigen presenting cells as prognostic markers for worsened outcome in OS. Furthermore, we show that IHC is a valid detection method for PD-L1 in OS. With up to 25% of OS patients expressing PD-L1, this study provides rational for targeting the PD-L1:PD-1 axis for immunotherapy in OS. Citation Format: Pratistha Koirala, Michael Roth, Jonathan Gill, Jordan Chinai, Sajida Piperdi, David Geller, Bang Hoang, Vincent Poon, Xingxing Zang, Richard Gorlick. Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4134.

Abstract 2445: Cytoplasmic mislocalization of p27 promotes metastasis and its autoantibody correlates with prognosis in osteosarcoma

Abstract Development of metastasis is the major cause of death in osteosarcoma, which is the most common malignant bone tumor in children and young adults. However, detection of metastasis relies solely on imaging techniques and targeted treatments of metastatic patients are still not available to improve the dismal outcome. Using an immunoproteomic approach, we identified that p27 autoantibody was significantly elevated in the plasma of high-risk osteosarcoma patients. Results of immunohistochemistry showed that cytoplasmic mislocalization of p27 occurred in a majority of osteosarcoma cases and in highly metastatic osteosarcoma cell lines. We demonstrated that ectopic expression of cytoplasmic p27 and shRNA-mediated gene silencing promoted and inhibited, respectively, the migration and invasion of osteosarcoma cells. Additionally, a mutation in S10 or T198, but not T157, phosphosite abolished the pro-migration and invasion phenotypes of cytoplasmic p27, possibly through a RhoA-related mechanism. Furthermore, mice injected with cells carrying cytoplasmic p27 increased the development of pulmonary metastasis when compared to an empty vector control. Lastly, using a large cohort of serum samples (n = 233), we showed that a higher level of the p27 autoantibody significantly correlated with poor overall and event-free survival of osteosarcoma (p &amp;lt; 0.05). Together, our results suggest that the circulating p27 autoantibody can be used as a prognostic biomarker at diagnosis and cytoplasmic mislocalization of p27 is a frequent event in osteosarcoma, which can promote tumor cell motility and invasiveness as well as metastasis formation. Targeting specific p27 phosphorylations may provide a novel therapeutic approach for osteosarcoma patients with metastasis. Citation Format: Manjula Nakka, Yiting Li, Aaron J. Kelly, Ching C. Lau, Mark Krailo, Donald A. Barkauskas, John Hicks, Tsz-Kwong Man. Cytoplasmic mislocalization of p27 promotes metastasis and its autoantibody correlates with prognosis in osteosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2445.

ΔNp63 mediates cellular survival and metastasis in canine osteosarcoma.

p63 is a structural homolog within the 53 family encoding two isoforms, ΔNp63 and TAp63. The oncogenic activity of ΔNp63 has been demonstrated in multiple cancers, however the underlying mechanisms that contribute to tumorigenesis are poorly characterized. Osteosarcoma (OSA) is the most common primary bone tumor in dogs, exhibiting clinical behavior and molecular biology essentially identical to its human counterpart. The purpose of this study was to evaluate the potential contribution of ΔNp63 to the biology of canine OSA. As demonstrated by qRT-PCR, nearly all canine OSA cell lines and tissues overexpressed ΔNp63 relative to normal control osteoblasts. Inhibition of ΔNp63 by RNAi selectively induced apoptosis in the OSA cell lines overexpressing ΔNp63. Knockdown of ΔNp63 upregulated expression of the proapoptotic Bcl-2 family members Puma and Noxa independent of p53. However the effects of ΔNp63 required transactivating isoforms of p73, suggesting that ΔNp63 promotes survival in OSA by repressing p73-dependent apoptosis. In addition, ΔNp63 modulated angiogenesis and invasion through its effects on VEGF-A and IL-8 expression, and STAT3 phosphorylation. Lastly, the capacity of canine OSA cell lines to form pulmonary metastasis was directly related to expression levels of ΔNp63 in a murine model of metastatic OSA. Together, these data demonstrate that ΔNp63 inhibits apoptosis and promotes metastasis, supporting continued evaluation of this oncogene as a therapeutic target in both human and canine OSA.

Down-regulation of microRNA-182 and microRNA-183 predicts progression of osteosarcoma.

IntroductionThe aim of this study was to investigate the expression levels of microRNA-182 and microRNA-183 and their association with clinicopathological features in patients with osteosarcoma.Material and methodsTotal RNA was purified from samples and noncancerous bone tissues and then quantitative real-time polymerase chain reaction was applied to evaluate the expression levels of microRNAs, and their relationship with clinicopathological features and survival in osteosarcoma patients.ResultsOur findings showed that expression of MiR-182 was clearly lower in osteosarcoma bone tissue (mean ± SD: 2.84 ±.07) compared with noncancerous bone tissues (6.23 ±1.72, p = 0.004). On the other hand, lower expression of MiR-183 was seen in osteosarcoma bone tissue (1.43 ±0.59) when compared with normal tissues (4.36 ±2.47, p = 0.036). Decreased expression of MiR-182 was clearly correlated with advanced clinical stage (p = 0.001), metastasis or recurrence (p = 0.024), and large tumor size (p = 0.032). Decreased expression of MiR-183 was associated with advanced TNM stage (p = 0.004), and metastasis or recurrence (p = 0.002). A multivariate Cox proportional hazards model revealed that low expression of MiR-182 and MiR-183 (p = 0.02; p = 0.016), TNM stage (p = 0.04), and metastasis or recurrence (p = 0.03) were significantly associated with poor survival as independent prognostic factors.ConclusionsThese findings suggest that MiR-182 and MiR-183 may be associated with progression and metastasis of osteosarcoma.

Diagnostic investigations of PLA2G16 and CDH11 expression levels as independent prognostic markers of human osteosarcoma.

IntroductionThe aim of this study was to facilitate and deepen the understanding of the associations of the clinical significance of PLA2G16 and CDH11 in patients with osteosarcoma.Material and methodsWe collected 50 paired osteosarcoma tissues and adjacent normal bone tissues and evaluated the expression of PLA2G16 and CDH11 by quantitavise reverse transcriptase real-time polymerase chain reaction.ResultsPLA2G16 expression was upregulated in osteosarcoma tissues when compared with adjacent normal bone tissues, and the difference was statistically significant (4.78 ±0.70 vs. 1.31 ±0.65; p < 0.05). Our data indicated that high expression of PLA2G16 was significantly related to advanced TNM stage and metastasis or recurrence (p < 0.05). The expression level of CDH11 was lower in osteosarcoma tissues (median relative expression level ± SD: 6.29 ±1.43) than adjacent normal bone tissues (mean ± SD: 13.72 ±3.08, p < 0.05). Our findings demonstrated that decreased expression of CDH11 was strongly linked to advanced TNM stage, and metastasis or recurrence (p < 0.05). Log-rank analysis showed that patients with high expression of PLA2G16 have shorter overall survival than those with low expression. Moreover, shorter overall survival was significantly correlated with decreased expression of CDH11. Multivariate Cox proportional hazards analysis showed that PLA2G16 (p = 0.028; HR = 2.621; 95% CI) and CDH11 (p = 0.023; HR = 2.81; 95% CI) expression and also metastasis or recurrence (p = 0.03; HR = 2.531; 95% CI) were independent prognostic factors for poor overall survival of osteosarcoma patients.ConclusionsThese findings suggest that PLA2G16 and CDH11 expression can be independent prognostic factors for poor overall survival of patients with osteosarcoma.

Improvement in High-Grade Osteosarcoma Survival: Results from 202 Patients Treated at a Single Institution in Taiwan.

The aim of this study was to compare survival before and after 2004 and define the prognostic factors for high-grade osteosarcomas beyond those of typical young patients with localized extremity disease.Few studies have reported the long-term treatment outcomes of high-grade osteosarcoma in Taiwan.A total of 202 patients with primary high-grade osteosarcoma who received primary chemotherapy at Taipei Veterans General Hospital between January 1995 and December 2011 were retrospectively evaluated and compared by period (1995–2003 vs 2004–2011). Patients of all ages and tumor sites and those following or not following controlled protocols were included in analysis of demographic, tumor-related, and treatment-related variables and survival.Overall survival and progression-free survival at 5 years were, respectively, 67.7% and 48% for all patients (n = 202), 77.3% and 57.1% for patients without metastasis (n = 157), and 33.9% and 14.8% for patients with metastasis (n = 45). The survival rates of patients treated after 2004 were significantly higher (by 13%–16%) compared with those of patients treated before 2004, with an accompanying 30% increase in histological good response rate (P = .002). Factors significantly contributing to inferior survival in univariate and multivariate analyses were diagnosis before 2004, metastasis at diagnosis, and being a noncandidate for a controlled treatment protocol.By comparison with the regimens used at our institution before 2004, the current results support the effectiveness of the post-2004 regimens, which consisted of substantially reduced cycles of high-dose methotrexate and a higher dosage of ifosfamide per cycle, cisplatin, and doxorubicin, for treating high-grade osteosarcoma in Asian patients.

YKL-40 protein in osteosarcoma tumor tissue.

YKL-40, a cellular glycoprotein isolated from the human osteosarcoma (OS) cell line MG63, is increased in the blood of patients with various types of cancer, and is found as an independent prognostic variable for survival. YKL-40 is also present with variable intensity in the tumor cells of some cancer types, but survival results have been conflicting. The aim of this study was to investigate the tissue expression of YKL-40 and its possible role as a predictive marker in patients with OS. Forty-eight patients were included in the study. Diagnostic biopsies were analyzed by immunohistochemistry; YKL-staining scores as well as CD14 and CD163 scores were determined, and survival data were determined statistically. A universal intense immunostaining for YKL-40 was found in all tumor cells, but tumor cell/stroma ratio varied, and this ratio (%) served as staining score. Using 24% as mean score to divide the material, patients with tumors of high YKL-40 score had a better survival than patients with low score (p = 0.05). YKL-positive macrophages had no influence on the result. Unexpectedly and contrary to some other findings in cancer tissues, this study has shown a correlation between high YKL-40 tumor cell/matrix ratio and longer overall survival in OS.

Evaluation of P-glycoprotein (Pgp) expression in human osteosarcoma by high-throughput tissue microarray.

Survival of osteosarcoma patients is currently limited by the development of metastases and multidrug resistance (MDR). A well-established cause of MDR involves overexpression of P-glycoprotein (Pgp) in tumor cells. However, some discrepancies still exist as to the clinical significance of Pgp in osteosarcoma. We sought to elucidate further whether the Pgp expression correlated with clinical behavior in a series of patients with osteosarcoma via high-throughput tissue microarray (TMA) analysis. Immunohistochemical analysis of Pgp expression in a TMA of 114 specimens with a retrospective review of 70 osteosarcoma patients admitted to the Massachusetts General Hospital (MGH) was performed. High Pgp expression was correlated with metastasis development and poor response to pre-operative chemotherapy in osteosarcoma patients. Eighteen of the fifty-seven patients initially admitted with primary osteosarcoma showed high Pgp expression. Among these 18 patients with high Pgp expression, 13 of 18 (72%) patients eventually developed metastases. There was no significant clinical relevance between Pgp expression and osteosarcoma survival. These results support that high expression of Pgp is important, but cannot be assigned as, an individual predictor in the development of human osteosarcoma. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1606-1612, 2016.

Expression of G Protein-coupled Receptor 56 Is an Unfavorable Prognostic Factor in Osteosarcoma Patients.

G protein-coupled receptor 56 (GPR56) is an atypical G protein-coupled receptor, with the long extracellular N-terminus. GPR56 can trigger various downstream signaling responsible for cell survival, proliferation, adhesion, and migration. Expression of GPR56 is associated with cell malignant transformation and tumor cell metastasis in several carcinomas such as melanoma and glioma. Osteosarcoma is the most common malignant bone tumor in adolescents and young adults with high metastasis tendency. The overall survival of osteosarcoma is unsatisfied, partially due to the lacking of predictive markers for metastasis and overall prognosis. This study aimed at figuring out whether expression of the GPR56 was associated with clinicopathological features of osteosarcoma. Eighty-nine patients who received osteosarcoma operation between March 2004 and February 2011 in Linyi People's Hospital were recruited. Immunohistochemical staining (IHC) was carried out to identify the expression of GPR56 in those osteosarcoma tissues, and our cohort was divided into higher-expression group and lower-expression group according to the cut-off of IHC score. Expression of GPR56 in osteosarcoma tissues was correlated with the TNM stage and overall survival. Univariate and multivariate analysis showed that GPR56 could act as an independent prognosis factor for osteosarcoma. Western blot results demonstrated that GPR56-siRNA down-regulated the expression of GTP-RhoA and Ki67. GTP-RhoA participates in the cell migration process, while Ki67 plays important roles in cell proliferation, indicating GPR56 may function in tumor development. Correspondingly, we show that GPR56 regulates the proliferation and invasion capacity of osteosarcoma cells. Our study has revealed the prognostic value of GPR56 expression in osteosarcoma.

Association of common variants in MTAP with susceptibility and overall survival of osteosarcoma: a two-stage population-based study in Han Chinese.

Osteosarcoma (OS) is a common malignant tumor, which exists widely in the bone of children and adolescents, and genetic factors may influence its susceptibility. Recently, the gene MTAP has been reported to be associated with OS in a Caucasian population. To investigate the association of common variants in MTAP with OS risk in Han Chinese individuals, we designed a two-stage case-control study with 392 OS patients and 1,578 unrelated healthy controls of Han Chinese individuals. A total of 17 tagging single nucleotide polymorphisms (SNPs) were firstly genotyped in the discovery stage, and single-SNP association and haplotypic association analyses have been performed. The SNP rs7023329 was found to be strongly associated with the OS risk (adjusted P = 0.002908), and the results of odds ratios (ORs) and 95% confidence intervals (CI) revealed increased risks from A allele of the SNP on OS (OR=1.33, 95% CI=1.13-1.62). The results were confirmed with a similar pattern in the validation stage (adjusted P = 0.006737, OR=1.49, 95% CI=1.11-2.00). Moreover, haplotypic analyses indicated that one haplotype block containing rs7023329 was significantly associated with OS risk in both stages (both global P<0.0001). The statistically significant association between the rs7023329 genotype and poor survival in OS patients was also observed. To sum up, our results prove that MTAP plays an important role in the etiology of OS, suggesting this gene as a potential genetic modifier for OS development.

MiR-205 functions as a tumor suppressor via targeting TGF-α in osteosarcoma

Osteosarcoma (OS) is the most common primary bone cancer, and it is most prevalent in children and young adults. The prognosis of OS remains poor, and survival of OS reached a plateau. The discovery of microRNAs (miRNAs) provides a new possibility for the early diagnosis and treatment of OS. In this study, we detected the expression level of miR-205 and Transforming growth factor-alpha (TGF-α) in 15 cases of clinical OS tissues and adjacent normal bone tissues. We found that the expression of miR-205 was significantly lower in OS tissues than in normal bone tissues; the expression of TGF-α mRNA was significantly increased in OS tissues than in normal bone tissues, the miR-205 was negatively correlated with TGF-α levels in both OS and normal bone tissues. Functional studies demonstrated that miR-205 significantly decreased the capability of cell proliferation, invasion and migration and induced G0/G1 growth arrest and apoptosis in OS cells. By using bioinformatics analytic tool (Targetscan), the 3'UTR of TGF-α gene was found to be a target of miR-205. Luciferase report assay further confirmed that TGF-α 3'UTR is a direct target of miR-205. We also found that the expression of TGF-α mRNA and protein was significantly down-regulated or up-regulated after miR-205 mimic or miR-205 inhibitor transfection. TGF-α knockdown study further showed that miR-205 regulated cell proliferation, invasion and migration by targeting TGF-α in OS. Enforced expression of TGF-α sufficiently restore the effects of miR-205 on cell proliferation, invasion and migration. In conclusion, our study suggested that miR-205 may function as a tumor suppressor via targeting TGF-α in OS, and the abnormal expression of miR-205 might be a key factor in OS progression.

Prognostic significance of CD44V6 expression in osteosarcoma: a meta-analysis.

Numerous individual studies evaluating the relationship between CD44V6 over-expression and prognostic impact in patients with osteosarcoma (OS) have yielded in conclusive results. This meta-analysis aimed to determine the value of cell adhesion molecule CD44V6 in prognosis of OS by conducting a systematic review and meta-analysis. A comprehensive search was conducted using PubMed (medline), Embase, ISI Web of Knowledge, Springer, the Cochrane Library, Scopus, BioMed Central, ScienceDirect, Wanfang, Weipu, and China National Knowledge Internet (CNKI) databases from inception through May 26, 2015. All available articles written in English or Chinese that investigated the expression of CD44V6 and the prognosis of OS were included. The quantity of the studies was evaluated according to the critical review checklist of the Dutch Cochrane Centre proposed by MOOSE. Finally, a total of eight studies with 486 OS patients were involved and the results indicated that the positive expression of CD44V6 predicts neoplasm metastasis (RR = 1.76, 95 % CI 1.38–2.25, p < 0.00001), and poor survival in OS with the pooled HR of 1.53 (95 % CI 1.25–1.88, p < 0.0001). No significant heterogeneity was observed among all studies. In conclusion, the present meta-analysis and systematic review strongly suggest that CD44V6 over-expression is associated with overall survival rate and metastasis in OS, and may be used as a prognostic biomarker to guide the clinical therapy for OS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13018-015-0328-z) contains supplementary material, which is available to authorized users.

Referral patterns, treatment and outcome of high-grade malignant bone sarcoma in Scandinavia--SSG Central Register 25 years' experience.

The objectives of this study were to present changes in referral patterns, treatment and survival in patients with high-grade malignant bone sarcoma in Sweden and Norway based on data in the Scandinavian Sarcoma Group (SSG) Central Register. Data on 1,437 patients with diagnosis 1986-2010 was analyzed. Osteosarcoma was the most frequentl diagnosis (45%), followed by Ewing sarcoma (21%) and chondrosarcoma (17%). Thirty-one percent of Swedish and 41% of Norwegian patients had tumors in the axial skeleton. Eighty-six percent of extremity tumors and 66% of axial tumors were referred to a sarcoma center prior to unplanned surgery or biopsy. During the past decade, limb salvage surgery has risen from under 50% to over 80%. Five-year overall survival in non-metastatic osteosarcoma was 70% for extremity tumors, and 35% for axial tumors. No improvement in osteosarcoma survival was observed during the last decade. Five-year survival in Ewing sarcoma improved from 50% to 69%. Referral patterns in bone sarcomas have improved. However, greater efforts should be dedicated to improving referral of patients with possible tumors in the axial skeleton to multidisciplinary teams (MDTs). Overall survival of patients with high-grade malignant bone sarcomas in Sweden and Norway is in line with other reports.